Acrivastine, [(E)-3-(6-[3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl]-2-pyridyl)-acrylic acid] is an analog of triprolidine (ACTIDIL.TM.) having the following chemical structure: ##STR1## (Cohen et al., 1985, Eur. J. Clin. Pharmacol. 28:197-204;Brogden and McTavish, 1991, Drugs 41:927-940). The drug is an H.sub.1 -receptor antagonist which has a rapid onset of action but is rather short acting. This makes acrivastine particularly appropriate for "on demand" therapy of subjects suffering from intermittent symptoms of, for example, allergic rhinitis (Brogden and McTavish, 1991, Drugs 41:927-940). Acrivastine has low sedating potential--however, mild sedation is observed under laboratory conditions at dosages of 8 and 16 mg using the multiple sleep latency test (id.). Undesirable drowsiness has been observed after administration of 8 mg of acrivastine, but was less than that associated with a related compound, triprolidine (id., citing Hamilton et al., 1985, Br. J. Clin. Pharmacol. 19:585 P-586 P). Prior to the present invention, there had been no systematic evaluation of the relationship between acrivastine pharmacokinetics and antihistaminic or sedative responses (Jallard et al., 1985, J. Clin. Pharmacol. 25:629-637).
Thus, one undesirable side effect of acrivastine is mild sedation. Acrivastine is currently administered in the United States at doses of 8 mg, three times a day in combination with 60 mg pseudoephedrine as SEMPREX-D.TM. capsules, as described in the 1996 Physicians Desk Reference, p. 468. Acrivastine is rapidly absorbed from the combination capsule following oral administration and peak plasma levels are obtained between 1 to 2 hours post-ingestion. Acrivastine has been shown to follow linear pharmacokinetics at ascending doses from 2 mg to 32 mg t.i.d. (Jallad et al., 1985, J. Clin. Pharmacol. 25:632). Following single dose oral administration of acrivastine 4 mg capsules and 12 mg oral solution to healthy volunteers, mean peak plasma concentrations (Cmax) of 73 and 179 ng/mL were attained at 1.4 and 0.85 hours (Tmax), respectively (Sifton et al., 1996, Physician's Desk Reference, 50th edition, Montvale, N.J.). Mean apparent volume of distribution (Vd/F) has been reported as 0.64 and 0.75 L/Kg following single and multiple doses, respectively. Acrivastine binding to human plasma proteins, primarily albumin, was 50.+-.2.0% and was concentration-independent over the range of 5 to 1000 ng/ml. The elimination half-life of acrivastine has been reported to be 1.7 hr, making it necessary to dose conventional, immediate-release formulations of acrivastine up to four times a day. Studies have shown that acrivastine is primarily eliminated by the kidneys. The principal active metabolite, a propionic acid analogue of acrivastine, is detected in plasma at concentrations well below those of parent compound (Brogden and McTavish, 1991, Drugs 6:927-940). Poor colonic absorption of acrivastine has led Balasubramanian et al. (1989, J. Clin. Pharmacol. 29:444-447) to suggest that development of sustained release formulations of acrivastine could be problematic.